This proposed project, which is submitted by a new investigator, will examine genetic influences on biological responses to nicotine in women using a pharmacogenetic paradigm. Specifically, this project will: (i) determine whether there are substantial genetic influences upon reactivity to nicotine in non-smokers, and (ii) examine the relationship between level of reactivity, progression to regular smoking and risk for dependence. Genetic influences upon nicotine reactivity will be determined within the context of a laboratory nicotine challenge protocol which will provide subjective, physiological and performance-based measures of nicotine responsivity in twin pairs stratified by smoking status. Monozygotic (MZ) and dizygotic (DZ) correlations in twin pairs concordant for non-smoking will be used to estimate the contributions of genes, shared environment and within-family environmental differences in experience to variability in measures of nicotine reactivity. Twin pairs can also be observed in smokers. The relationship between nicotine reactivity and risk for dependence will be evaluated by estimating the correlations, stratified by zygosity, of the responses to nicotine in non-smoking twins drawn from smoking-discordant twin pairs with the level of dependence evidenced by the smoking co-twin. Dependence will be defines as score on the modified Fagerstrom FTND Dependence scale. To enhance statistical power, same-sex full siblings of smoking twins will also be tested whenever available. Previous epidemiological studies have indicated that at least some factors influencing smoking dependence appear to be substantially heritable. Data obtained from the proposed project may facilitate the elucidation of critical (phenotypic) differences in biological responses to nicotine. These results could subsequently be used to inform future studies examining the genetics of smoking dependence and persistence and may also impact the development of appropriately targeted smoking prevention and cessation interventions.